Mission Statement

As part of the federal government’s National Institutes of Health (NIH), the National Eye Institute’s mission is to “conduct and support research, training, health information dissemination, and other programs with respect to blinding eye diseases, visual disorders, mechanisms of visual function, preservation of sight, and the special health problems and requirements of the blind.”

Molecular Immunology

The Section’s work has focused on understanding molecular and cellular mechanisms that regulate immune homeostasis, with particular emphasis on epigenetic mechanisms that regulate lymphocyte development and cell-fate decisions and roles played by pro-inflammatory and anti-inflammatory cytokines in the development of central nervous system (CNS) inflammatory diseases. This Section is part of the Laboratory of Immunology.

The Molecular Immunology Section seeks to understand molecular and cellular mechanisms that regulate host immunity with particular focus on lymphocytes that mediate CNS autoimmune diseases, such as Uveitis and Multiple Sclerosis. Major interest is on: Auto-reactive lymphocytes that mediate remitting and recurrent CNS autoimmune diseases; Development of Biologics and cytokine-based therapies for autoimmune and neurodegenerative diseases; Role of JAK/STAT signal transduction pathway and suppressors of cytokine signaling (SOCS) proteins in the regulation of lymphocyte development and cell-fate decisions. Major Areas of Investigation and Findings:(i) Auto-reactive lymphocytes that mediate CNS autoimmune diseases Intraocular inflammatory diseases (Uveitis) are a major cause of severe visual handicap and include sight-threatening idiopathic inflammatory ocular disease such as Behcet disease, birdshot retinochoroidopathy, Vogt-Koyanagi-Harada, sympathetic ophthalmia and ocular sarcoidosis. Uveitis may be of infectious or autoimmune etiology. Similar to other organ-specific autoimmune diseases such multiple sclerosis, Uveitis is characterized by repeated cycles of remission and recurrent inflammation. We established that Th17 cells might be the etiologic agents of uveitis by studies showing that blood of patients with uveitis contain more Th17 cells than that of healthy individuals and the expansion of Th17 is inhibited in part by immunosuppressive cytokines. A great deal of our effort is now devoted to studies aimed at understanding factors that promote Th17-mediated uveitis and mechanisms by which anti-inflammatory cytokines including IL-27 and IL-35 inhibit uveitis and mitigate ocular pathology. (ii) Development of Biologics for treating autoimmune diseases IL-12 family cytokines have emerged as important players in the development of CNS autoimmune diseases. Each member is comprised of an alpha and beta chain and 4 heterodimeric IL-12 cytokines have been described, with some members (IL-12, IL-23) promoting autoimmune pathology while others (IL-27, IL-35) suppress inflammation and limit tissue injury. A major goal of our drug discovery program is to genetically engineer each  and  IL-12 subunit protein and novel combinations of these subunits for use as potential therapeutic cytokines. To this end we have genetically engineered: (i) Recombinant mouse IL-35; (ii) Novel IL-12 member (IL-39); (iii) Novel rIL27p28/IL12p40 fusokine; (iv) rIL12p35, rIL12p40; rIL27p28; and rEbi3 single chain proteins. We have shown that; (i) rIL-35, rIL-27 or rIL27p28/IL12p40 inhibits Uveitis; (ii) rIL12p35 and Ebi3 suppresses lymphocyte proliferation and IL-39 producing B cells maybe the etiologic agent of systemic Lupus Erythematosus (SLE). These proof-of-concept studies suggest that cytokines comprising of unique IL-12 α and β subunits pairing may constitute a new class of therapeutic cytokines or therapeutic targets. (iii) Mechanisms that regulate lymphocyte development and cell-fate decisions The innate and adoptive immune systems have distinct functions in host immunity. The innate immune system provides instructional signals for lymphocyte differentiation while lymphocytes regulate the intensity and duration of the inflammatory response by coordinating activities of most immune cells. Innate and adaptive immune cell function is mediated by cytokines, signaling proteins that allow cells to communicate with other cell types and movement of immune cells towards sites of inflammation, infection and trauma. Most cytokines activate the JAK/STAT signal transduction pathway, an evolutionarily conserved mechanism that regulates lymphocyte development, differentiation and lineage commitment. On the other hand, the initiation, duration and intensity of JAK/STAT signaling is under stringent feedback regulation by suppressors of cytokine signaling (SOCS) proteins and diverse array of pathologic conditions including immunodeficiency and autoimmune diseases arise from aberrant regulation of the JAK/STAT proteins. We have and continue to characterize JAK/STAT signaling pathways of resident ocular cells and inflammatory cells that mediate ocular diseases using cell lines or primary cells and validate our findings in transgenic and knockout mouse and rat models.